Abstract
Breast cancer brain metastases remain a significant clinical problem. Chemotherapy is ineffective and a lack of treatment options result in poor patient outcomes. Targeted therapeutics have proven to be highly effective in primary breast cancer, but lack of molecular genomic characterization of metastatic brain tumors is hindering the development of new treatment regimens. Here we contribute to fill this void by reporting on gene copy number variation (CNV) in 10 breast cancer metastatic brain tumors, assayed by array comparative genomic hybridization (aCGH). Results were compared to a list of cancer genes verified by others to influence cancer. Cancer gene aberrations were identified in all specimens and pathway-level analysis was applied to aggregate data, which identified stem cell pluripotency pathway enrichment and highlighted recurring, significant amplification of SOX2, PIK3CA, NTRK1, GNAS, CTNNB1, and FGFR1. For a subset of the metastatic brain tumor samples (n = 4) we compared patient-matched primary breast cancer specimens. The results of our CGH analysis and validation by alternative methods indicate that oncogenic signals driving growth of metastatic tumors exist in the original cancer. This report contributes support for more rapid development of new treatments of metastatic brain tumors, the use of genomic-based diagnostic tools and repurposed drug treatments.
Highlights
Despite advances in the treatments for breast cancer, effective treatments for brain metastases remain elusive
An examination of the biomedical literature reveals a relative lack of molecular genomic characterization of brain metastases [5], which could lead to effective therapeutic interventions and better patient outcomes as evidenced by advancements in therapies guided by molecular targets to treat primary breast tumors, e.g., drugs targeting estrogen receptor-alpha (ERα) or the epidermal growth factor receptor ERBB2/HER2 [6]
Macro-colonization is described as the rate-limiting step in metastatic tumor formation, accounting for fewer than 0.1% of cancer cells that enter the circulatory system [13,14,15,16]. This suggests that the spectrum of mutationactivated oncogenes driving the processes of colonization and/or metastatic tumor outgrowth is limited, and that causative lesions would be recurrent in patient specimens
Summary
Despite advances in the treatments for breast cancer, effective treatments for brain metastases remain elusive. The brain presents a unique and complex tissue microenvironment and the colonization and formation of metastatic tumors depends on interactions of the properties of the microenvironment and the phenotype of the colonizing metastatic breast cancer cells [3, 4]. This concept must be reconciled with knowledge that cancer is a genetic disease with pathobiology driven by somatic gene mutations, i.e., gain-of-function mutations www.impactjournals.com/oncotarget in oncogenes and loss-of-function mutations in tumor suppressors. The projected feasibility of molecularly-targeted therapies for metastatic brain tumors is supported by a growing body of empirical evidence that small tyrosine kinase inhibitors and antigen-targeted drugs can traverse the blood-brain barrier and result in clinical benefit for patients harboring metastatic brain lesions [7,8,9,10,11,12]
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